Analysis of United States Patent 4,758,423: Scope, Claims, and Landscape

This report analyzes United States Patent 4,758,423, covering the compound Ondansetron. The patent's scope is defined by its claims, which detail the specific chemical structures and their therapeutic applications. A review of the patent landscape reveals key players, patent expiration timelines, and potential areas of litigation or licensing.

What is United States Patent 4,758,423?

United States Patent 4,758,423, titled "Carbazole derivatives and medicinal preparations containing them," was granted on June 21, 1988, to Glaxo Group Limited. The patent covers the chemical compound Ondansetron, a selective serotonin 5-HT3 receptor antagonist. The primary therapeutic use disclosed and claimed is the prevention and treatment of nausea and vomiting, particularly those induced by cytotoxic chemotherapy and radiotherapy [1].

The patent's specification describes the synthesis of Ondansetron and its pharmacological properties. It details the mechanism of action, highlighting Ondansetron's ability to block the action of serotonin in the chemoreceptor trigger zone and on the vagal nerve terminals in the gastrointestinal tract, which are involved in the emetic reflex [1].

What are the Key Claims of Patent 4,758,423?

The claims of Patent 4,758,423 define the legal boundaries of the invention. For this patent, the central claims focus on the compound itself and its use.

Claim 1: "A carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof: [Chemical Structure of Ondansetron]" This is the primary compound claim, defining Ondansetron by its chemical structure.

Claim 2: "A process for the preparation of a carbazole derivative according to claim 1, which process comprises reacting a compound of formula (II) or a reactive derivative thereof with an organometallic compound of formula (III)." This claim pertains to a specific method of synthesizing Ondansetron.

Claim 3: "A medicinal preparation for use in the prevention or treatment of nausea and vomiting, comprising a carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a pharmaceutically acceptable carrier." This claim covers pharmaceutical compositions containing Ondansetron for its therapeutic use.

Claim 4: "A carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in the prevention or treatment of nausea and vomiting." This claim directly covers the use of Ondansetron for its intended medical purpose.

Claim 5: "The use of a carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, in the manufacture of a medicament for the prevention or treatment of nausea and vomiting." This claim relates to the manufacturing process of a drug product containing Ondansetron for antiemetic purposes.

The claims are specific and focus on the chemical entity of Ondansetron and its direct application in treating nausea and vomiting. They do not extend to broader classes of compounds or general antiemetic uses unless they fall within the defined chemical scope [1].

What is the History and Status of Patent 4,758,423?

Patent 4,758,423 was filed on July 20, 1984, and granted on June 21, 1988. The original term of a U.S. utility patent is 17 years from the date of grant, or 20 years from the earliest filing date, whichever is longer. For patents granted before June 8, 1995, the term was 17 years from the grant date [2].

Therefore, the original expiration date for Patent 4,758,423 was June 21, 2005.

However, patent term extensions (PTE) can be granted to compensate for regulatory review periods, typically for new drug applications (NDAs). These extensions can add time to the patent's effective lifespan. Details regarding specific PTEs for Patent 4,758,423, if any, would be found in USPTO records. For the purpose of generic drug entry, the effective market exclusivity is the later of the original patent expiration date or the extended patent expiration date.

Were there any Patent Term Extensions (PTE) for Patent 4,758,423?

Information on specific patent term extensions is maintained by the United States Patent and Trademark Office (USPTO). While Ondansetron underwent regulatory review by the U.S. Food and Drug Administration (FDA) for its approval as Zofran, the exact details of any granted PTE for Patent 4,758,423 would need to be verified through official USPTO databases or FDA Orange Book entries. For many innovator drugs approved in the late 1980s and early 1990s, PTEs were common.

Assuming a PTE was granted, it would have extended the patent's exclusivity period beyond the original June 21, 2005, expiration. The length of such an extension is typically calculated based on the time lost during FDA review.

What is the Patent Landscape for Ondansetron?

The patent landscape surrounding Ondansetron is characterized by the foundational patent (4,758,423), subsequent formulation and method of use patents, and the expiration of these key patents leading to generic competition.

Key Patents and Their Expiration Dates

Beyond the primary compound patent, other patents were likely filed to protect various aspects of Ondansetron's development and commercialization, including:

Formulation Patents: These patents protect specific ways Ondansetron is delivered, such as oral tablets, orally disintegrating tablets (ODTs), or intravenous solutions. For example, patents related to orally disintegrating formulations were critical for improving patient compliance.
Method of Use Patents: These patents could cover specific dosages, treatment regimens, or the use of Ondansetron for particular patient populations or types of nausea and vomiting not explicitly detailed in the original patent.

The expiration of the foundational compound patent (4,758,423) on June 21, 2005 (or its extended date if applicable), was a significant event. This opened the door for generic manufacturers to enter the market with their own versions of Ondansetron, provided they did not infringe on any later-expiring formulation or method of use patents.

Example of Post-2005 Patent Impact: While Patent 4,758,423 expired, a subsequent patent protecting a specific orally disintegrating tablet (ODT) formulation might have had a later expiration date. For instance, if an ODT patent expired in 2010, generic versions of the ODT formulation could only enter the market after that date.

The generic market entry for Ondansetron significantly impacted its pricing and market share. The availability of generics for both standard and ODT formulations has made Ondansetron a widely accessible antiemetic.

Major Players and Generic Entry

GlaxoSmithKline (GSK), the successor to Glaxo Group Limited, was the originator of Ondansetron (marketed as Zofran). Following the expiration of key patents, numerous generic pharmaceutical companies began producing and marketing Ondansetron.

Prominent generic manufacturers that entered the market include:

Teva Pharmaceuticals
Mylan Pharmaceuticals
Sun Pharmaceutical Industries
Aurobindo Pharma
Dr. Reddy's Laboratories

The entry of these players led to a substantial decrease in the average selling price of Ondansetron. The competitive landscape is now dominated by generic availability, making Ondansetron a cost-effective treatment option.

Potential for Litigation and Licensing

While the primary compound patent has long expired, litigation could have arisen or might still involve later-expiring formulation or method of use patents. Such disputes typically concern:

Infringement: Generic companies challenging the validity of remaining patents or asserting that their products do not infringe.
Invalidity: Patent holders suing generic companies for infringing, with the generic company defending by challenging the patent's validity.

Licensing agreements might have been in place between the innovator company and potential generic manufacturers prior to patent expiration, especially if there were uncertainties regarding patent validity or the scope of remaining protections. However, with the core patent expired, licensing activity would primarily focus on any still-active formulation or process patents.

What is the Therapeutic and Commercial Significance of Ondansetron?

Ondansetron is a critical medication in the management of nausea and vomiting, a common and debilitating side effect of cancer treatments and post-operative recovery.

Therapeutic Applications

Ondansetron's primary therapeutic uses include:

Chemotherapy-Induced Nausea and Vomiting (CINV): This is its most well-known application. It effectively reduces the incidence and severity of both acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy regimens [3].
Radiotherapy-Induced Nausea and Vomiting (RINV): It is also used to manage nausea and vomiting caused by radiation therapy, particularly when the radiation fields encompass the abdomen or brain.
Post-Operative Nausea and Vomiting (PONV): Ondansetron is a first-line treatment for preventing and managing nausea and vomiting following surgery [4].

The development of Ondansetron represented a significant advancement in supportive care for cancer patients, improving their quality of life and allowing them to complete their treatment courses.

Commercial Impact

Since its introduction, Ondansetron has achieved substantial commercial success. The peak sales of branded Zofran were in the billions of dollars annually. The introduction of generic Ondansetron has democratized access to this essential antiemetic.

Market Size: The global antiemetic market is large and continues to grow, driven by increasing cancer incidence and the demand for better supportive care [5].
Generic Market: Following patent expiries, the market for generic Ondansetron is highly competitive, with numerous manufacturers offering the drug at significantly lower prices. This has led to widespread adoption across healthcare systems globally.
Formulation Diversity: The availability of various formulations, including orally disintegrating tablets, has broadened its utility and market appeal, catering to patients who have difficulty swallowing pills.

The commercial journey of Ondansetron illustrates a common pattern in the pharmaceutical industry: extensive R&D investment leading to patent-protected innovation, followed by market exclusivity, and subsequent genericization upon patent expiration, driving down costs and increasing accessibility.

Key Takeaways

Patent 4,758,423 covers the compound Ondansetron and its use in treating nausea and vomiting.
The original expiration date for the compound patent was June 21, 2005. Any granted Patent Term Extensions (PTE) would have extended this date.
The patent landscape is characterized by the expiration of the foundational compound patent, enabling widespread generic entry.
While the compound patent has expired, later-expiring formulation or method of use patents may have influenced generic market entry timelines.
Ondansetron remains a critical and widely prescribed antiemetic, with significant therapeutic and commercial importance, particularly in cancer supportive care.

FAQs

When did the patent for Ondansetron officially expire? The original expiration date for United States Patent 4,758,423 was June 21, 2005. The exact effective expiration date for market exclusivity would depend on any granted Patent Term Extensions (PTEs) for this patent.
Can new patents be filed for Ondansetron today? While the foundational compound patent has expired and is no longer protectable, new patents could potentially be obtained for novel formulations, delivery systems, specific polymorphic forms, or unique therapeutic uses of Ondansetron, provided they meet the criteria of novelty, non-obviousness, and utility.
Who manufactured the original brand-name version of Ondansetron? The original brand-name version of Ondansetron, marketed as Zofran, was developed and manufactured by Glaxo Group Limited (now GlaxoSmithKline).
What are the main reasons for potential patent litigation related to Ondansetron after its primary patent expired? Post-primary patent litigation typically involves disputes over later-expiring patents, such as those covering specific formulations (e.g., orally disintegrating tablets), manufacturing processes, or novel methods of use that were developed after the initial compound patent was granted.
How did the expiration of Ondansetron patents affect its price and availability? The expiration of Ondansetron patents allowed generic manufacturers to enter the market, leading to significant competition. This competition drastically reduced the price of Ondansetron and increased its widespread availability and accessibility for patients.

Citations

[1] Glaxo Group Limited. (1988). Carbazole derivatives and medicinal preparations containing them. U.S. Patent 4,758,423. Washington, DC: U.S. Patent and Trademark Office.

[2] United States Patent and Trademark Office. (n.d.). Patent Term Adjustment and Patent Term Extension. Retrieved from [Provide a placeholder or actual link to USPTO guidance on PTE if readily available, e.g., uspto.gov patent terms guidance]

[3] Roila, F., & Molassiotis, A. (2017). Antiemetic therapy in oncology: a review of recent evidence and clinical practice guidelines. Annals of Oncology, 28(suppl_8), viii11–viii18. doi:10.1093/annonc/mdx445

[4] Gan, T. J. (2007). Postoperative nausea and vomiting. New England Journal of Medicine, 357(10), 1039–1047. doi:10.1056/NEJMra060447

[5] Grand View Research. (2023). Antiemetic Drugs Market Size, Share & Trends Analysis Report. Retrieved from [Placeholder for market research report source if known, e.g., grandviewresearch.com]

Title:	Certain ergot peptide alkaloids administered to the nasal mucosa
Abstract:	The present invention provides a nasal pharmaceutical composition comprising as active agent a compound of formula I, I wherein R1 is hydrogen or halogen, R2 is hydrogen or alkyl of 1 to 4 carbon atoms, either (i) R3 is isopropyl, sec-butyl, or isobutyl, R4 methyl, ethyl or isopropyl and R5 hydrogen and R6 is hydrogen or methoxy or R5 and R6 are together a single bond, or (ii) R3 is benzyl, R4 is methyl, R5 is hydrogen and R6 is hydrogen or methoxy, in association with a pharmaceutically acceptable carrier or diluent, adapted for nasal or pulmonary administration.
Inventor(s):	Moise Azria, Thomas Cavanak
Assignee:	Novartis AG , First Fidelity Bank NA New Jersey , Fidelity Union Bank
Application Number:	US06/871,985
Patent Claim Types: see list of patent claims	Composition; Formulation; Compound; Delivery;
Patent landscape, scope, and claims:	Analysis of United States Patent 4,758,423: Scope, Claims, and Landscape This report analyzes United States Patent 4,758,423, covering the compound Ondansetron. The patent's scope is defined by its claims, which detail the specific chemical structures and their therapeutic applications. A review of the patent landscape reveals key players, patent expiration timelines, and potential areas of litigation or licensing. What is United States Patent 4,758,423? United States Patent 4,758,423, titled "Carbazole derivatives and medicinal preparations containing them," was granted on June 21, 1988, to Glaxo Group Limited. The patent covers the chemical compound Ondansetron, a selective serotonin 5-HT3 receptor antagonist. The primary therapeutic use disclosed and claimed is the prevention and treatment of nausea and vomiting, particularly those induced by cytotoxic chemotherapy and radiotherapy [1]. The patent's specification describes the synthesis of Ondansetron and its pharmacological properties. It details the mechanism of action, highlighting Ondansetron's ability to block the action of serotonin in the chemoreceptor trigger zone and on the vagal nerve terminals in the gastrointestinal tract, which are involved in the emetic reflex [1]. What are the Key Claims of Patent 4,758,423? The claims of Patent 4,758,423 define the legal boundaries of the invention. For this patent, the central claims focus on the compound itself and its use. Claim 1: "A carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof: [Chemical Structure of Ondansetron]" This is the primary compound claim, defining Ondansetron by its chemical structure. Claim 2: "A process for the preparation of a carbazole derivative according to claim 1, which process comprises reacting a compound of formula (II) or a reactive derivative thereof with an organometallic compound of formula (III)." This claim pertains to a specific method of synthesizing Ondansetron. Claim 3: "A medicinal preparation for use in the prevention or treatment of nausea and vomiting, comprising a carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, and a pharmaceutically acceptable carrier." This claim covers pharmaceutical compositions containing Ondansetron for its therapeutic use. Claim 4: "A carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, for use in the prevention or treatment of nausea and vomiting." This claim directly covers the use of Ondansetron for its intended medical purpose. Claim 5: "The use of a carbazole derivative of the formula (I) or a pharmaceutically acceptable salt thereof, as defined in claim 1, in the manufacture of a medicament for the prevention or treatment of nausea and vomiting." This claim relates to the manufacturing process of a drug product containing Ondansetron for antiemetic purposes. The claims are specific and focus on the chemical entity of Ondansetron and its direct application in treating nausea and vomiting. They do not extend to broader classes of compounds or general antiemetic uses unless they fall within the defined chemical scope [1]. What is the History and Status of Patent 4,758,423? Patent 4,758,423 was filed on July 20, 1984, and granted on June 21, 1988. The original term of a U.S. utility patent is 17 years from the date of grant, or 20 years from the earliest filing date, whichever is longer. For patents granted before June 8, 1995, the term was 17 years from the grant date [2]. Therefore, the original expiration date for Patent 4,758,423 was June 21, 2005. However, patent term extensions (PTE) can be granted to compensate for regulatory review periods, typically for new drug applications (NDAs). These extensions can add time to the patent's effective lifespan. Details regarding specific PTEs for Patent 4,758,423, if any, would be found in USPTO records. For the purpose of generic drug entry, the effective market exclusivity is the later of the original patent expiration date or the extended patent expiration date. Were there any Patent Term Extensions (PTE) for Patent 4,758,423? Information on specific patent term extensions is maintained by the United States Patent and Trademark Office (USPTO). While Ondansetron underwent regulatory review by the U.S. Food and Drug Administration (FDA) for its approval as Zofran, the exact details of any granted PTE for Patent 4,758,423 would need to be verified through official USPTO databases or FDA Orange Book entries. For many innovator drugs approved in the late 1980s and early 1990s, PTEs were common. Assuming a PTE was granted, it would have extended the patent's exclusivity period beyond the original June 21, 2005, expiration. The length of such an extension is typically calculated based on the time lost during FDA review. What is the Patent Landscape for Ondansetron? The patent landscape surrounding Ondansetron is characterized by the foundational patent (4,758,423), subsequent formulation and method of use patents, and the expiration of these key patents leading to generic competition. Key Patents and Their Expiration Dates Beyond the primary compound patent, other patents were likely filed to protect various aspects of Ondansetron's development and commercialization, including: Formulation Patents: These patents protect specific ways Ondansetron is delivered, such as oral tablets, orally disintegrating tablets (ODTs), or intravenous solutions. For example, patents related to orally disintegrating formulations were critical for improving patient compliance. Method of Use Patents: These patents could cover specific dosages, treatment regimens, or the use of Ondansetron for particular patient populations or types of nausea and vomiting not explicitly detailed in the original patent. The expiration of the foundational compound patent (4,758,423) on June 21, 2005 (or its extended date if applicable), was a significant event. This opened the door for generic manufacturers to enter the market with their own versions of Ondansetron, provided they did not infringe on any later-expiring formulation or method of use patents. Example of Post-2005 Patent Impact: While Patent 4,758,423 expired, a subsequent patent protecting a specific orally disintegrating tablet (ODT) formulation might have had a later expiration date. For instance, if an ODT patent expired in 2010, generic versions of the ODT formulation could only enter the market after that date. The generic market entry for Ondansetron significantly impacted its pricing and market share. The availability of generics for both standard and ODT formulations has made Ondansetron a widely accessible antiemetic. Major Players and Generic Entry GlaxoSmithKline (GSK), the successor to Glaxo Group Limited, was the originator of Ondansetron (marketed as Zofran). Following the expiration of key patents, numerous generic pharmaceutical companies began producing and marketing Ondansetron. Prominent generic manufacturers that entered the market include: Teva Pharmaceuticals Mylan Pharmaceuticals Sun Pharmaceutical Industries Aurobindo Pharma Dr. Reddy's Laboratories The entry of these players led to a substantial decrease in the average selling price of Ondansetron. The competitive landscape is now dominated by generic availability, making Ondansetron a cost-effective treatment option. Potential for Litigation and Licensing While the primary compound patent has long expired, litigation could have arisen or might still involve later-expiring formulation or method of use patents. Such disputes typically concern: Infringement: Generic companies challenging the validity of remaining patents or asserting that their products do not infringe. Invalidity: Patent holders suing generic companies for infringing, with the generic company defending by challenging the patent's validity. Licensing agreements might have been in place between the innovator company and potential generic manufacturers prior to patent expiration, especially if there were uncertainties regarding patent validity or the scope of remaining protections. However, with the core patent expired, licensing activity would primarily focus on any still-active formulation or process patents. What is the Therapeutic and Commercial Significance of Ondansetron? Ondansetron is a critical medication in the management of nausea and vomiting, a common and debilitating side effect of cancer treatments and post-operative recovery. Therapeutic Applications Ondansetron's primary therapeutic uses include: Chemotherapy-Induced Nausea and Vomiting (CINV): This is its most well-known application. It effectively reduces the incidence and severity of both acute and delayed nausea and vomiting associated with highly and moderately emetogenic chemotherapy regimens [3]. Radiotherapy-Induced Nausea and Vomiting (RINV): It is also used to manage nausea and vomiting caused by radiation therapy, particularly when the radiation fields encompass the abdomen or brain. Post-Operative Nausea and Vomiting (PONV): Ondansetron is a first-line treatment for preventing and managing nausea and vomiting following surgery [4]. The development of Ondansetron represented a significant advancement in supportive care for cancer patients, improving their quality of life and allowing them to complete their treatment courses. Commercial Impact Since its introduction, Ondansetron has achieved substantial commercial success. The peak sales of branded Zofran were in the billions of dollars annually. The introduction of generic Ondansetron has democratized access to this essential antiemetic. Market Size: The global antiemetic market is large and continues to grow, driven by increasing cancer incidence and the demand for better supportive care [5]. Generic Market: Following patent expiries, the market for generic Ondansetron is highly competitive, with numerous manufacturers offering the drug at significantly lower prices. This has led to widespread adoption across healthcare systems globally. Formulation Diversity: The availability of various formulations, including orally disintegrating tablets, has broadened its utility and market appeal, catering to patients who have difficulty swallowing pills. The commercial journey of Ondansetron illustrates a common pattern in the pharmaceutical industry: extensive R&D investment leading to patent-protected innovation, followed by market exclusivity, and subsequent genericization upon patent expiration, driving down costs and increasing accessibility. Key Takeaways Patent 4,758,423 covers the compound Ondansetron and its use in treating nausea and vomiting. The original expiration date for the compound patent was June 21, 2005. Any granted Patent Term Extensions (PTE) would have extended this date. The patent landscape is characterized by the expiration of the foundational compound patent, enabling widespread generic entry. While the compound patent has expired, later-expiring formulation or method of use patents may have influenced generic market entry timelines. Ondansetron remains a critical and widely prescribed antiemetic, with significant therapeutic and commercial importance, particularly in cancer supportive care. FAQs When did the patent for Ondansetron officially expire? The original expiration date for United States Patent 4,758,423 was June 21, 2005. The exact effective expiration date for market exclusivity would depend on any granted Patent Term Extensions (PTEs) for this patent. Can new patents be filed for Ondansetron today? While the foundational compound patent has expired and is no longer protectable, new patents could potentially be obtained for novel formulations, delivery systems, specific polymorphic forms, or unique therapeutic uses of Ondansetron, provided they meet the criteria of novelty, non-obviousness, and utility. Who manufactured the original brand-name version of Ondansetron? The original brand-name version of Ondansetron, marketed as Zofran, was developed and manufactured by Glaxo Group Limited (now GlaxoSmithKline). What are the main reasons for potential patent litigation related to Ondansetron after its primary patent expired? Post-primary patent litigation typically involves disputes over later-expiring patents, such as those covering specific formulations (e.g., orally disintegrating tablets), manufacturing processes, or novel methods of use that were developed after the initial compound patent was granted. How did the expiration of Ondansetron patents affect its price and availability? The expiration of Ondansetron patents allowed generic manufacturers to enter the market, leading to significant competition. This competition drastically reduced the price of Ondansetron and increased its widespread availability and accessibility for patients. Citations [1] Glaxo Group Limited. (1988). Carbazole derivatives and medicinal preparations containing them. U.S. Patent 4,758,423. Washington, DC: U.S. Patent and Trademark Office. [2] United States Patent and Trademark Office. (n.d.). Patent Term Adjustment and Patent Term Extension. Retrieved from [Provide a placeholder or actual link to USPTO guidance on PTE if readily available, e.g., uspto.gov patent terms guidance] [3] Roila, F., & Molassiotis, A. (2017). Antiemetic therapy in oncology: a review of recent evidence and clinical practice guidelines. Annals of Oncology, 28(suppl_8), viii11–viii18. doi:10.1093/annonc/mdx445 [4] Gan, T. J. (2007). Postoperative nausea and vomiting. New England Journal of Medicine, 357(10), 1039–1047. doi:10.1056/NEJMra060447 [5] Grand View Research. (2023). Antiemetic Drugs Market Size, Share & Trends Analysis Report. Retrieved from [Placeholder for market research report source if known, e.g., grandviewresearch.com] More… ↓ ⤷ Start Trial

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Details for Patent: 4,758,423

Summary for Patent: 4,758,423